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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-03-0778.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
From Medizinische Klinik des Klinikums Rechts der Isar
und Deutsches Herzzentrum, Technische Universität München,
Munich, Germany; Institut für Biochemie, Fachbereich
Humanmedizin, Justus-Liebig-Universität, Giessen,
Germany; and the Finsen Laboratory, Rigshospitalet,
Copenhagen, Denmark.
The urokinase receptor (urokinase plasminogen activator receptor;
uPAR) regulates monocyte adhesion by direct binding to vitronectin and by forming complexes with integrins. Therefore, possible
up-regulation of uPAR in acute myocardial infarction (AMI) may affect
monocyte adhesion. In 20 patients with AMI, uPAR surface expression
(measured by flow cytometry) was increased compared with that in
patients with chronic stable angina (mean ± SD
fluorescence, 179 ± 96 vs 80 ± 53; P = .002).
Expression of uPAR correlated with activation of
Activated monocytes play a key role in the
pathophysiology of atherosclerosis and acute myocardial infarction
(AMI).1 To exert their local inflammatory potential,
monocytes must attach to the vessel wall and emigrate to the site of
inflammation. The complexity of this process requires the concerted
interaction of adhesion receptors and their respective coreceptors or
counter-receptors.2 The urokinase receptor (urokinase
plasminogen activator receptor [uPAR], CD87) regulates monocyte
adhesion by direct binding to the extracellular matrix protein
vitronectin3,4 and by regulating the function of the
In AMI, proinflammatory cytokines such as interleukin-1 Reagents
Patients
Cells Mononuclear cells (MNCs) were isolated from patients by Ficoll gradient centrifugation (20 minutes at 4°C at 800g). Human umbilical vein endothelial cells (HUVECs; PromoCell, Heidelberg, Germany) were cultured (2 to 4 passages) in low-serum endothelial cell growth medium (PromoCell) on gelatin-coated tissue-culture plastic. BAF3 cells (mouse pre-B lymphocytes), which do not express uPAR, were from the American Type Culture Collection (Rockville, MD). The BAF3 cells were cultured in RPMI 1640 containing 10% (vol/vol) fetal-calf serum (FCS), 100 U/mL penicillin, 100 µg/mL streptomycin (Gibco, Grand Island, NY), and 2 ng/mL IL-3 (Stratham Biotech, Hannover, Germany) and were stably transfected with uPAR complementary DNA (cDNA) by electroporation (BioRad, Munich, Germany). Cells were selected in the presence of 1.0 mg/mL G418 (Calbiochem, Bad Soden, Germany) and characterized for uPAR expression by flow cytometry and Western blot analysis. Nontransfected cells and 4 clones showing different expression of uPAR were used for subsequent experiments. Human monocytic MonoMac6 cells18 were cultured in VLE-RPMI-1640 (Biochrom, Berlin, Germany) containing 10% low-toxin FCS (Clonetics, Taufkirchen, Germany).Adhesion assays Adhesion assays were performed as described previously.9,19Cell-to-cell adhesion. HUVECs were seeded on gelatin-coated, 96-well plates for 48 hours. Confluency was confirmed by microscopical inspection before each experiment. Freshly isolated MNCs or MonoMac6 cells were washed twice in adhesion medium (25 mM serum-free RPMI 1640 and HEPES [N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid]) and given various pretreatments. Cells (7 × 105/mL) were coincubated with HUVEC monolayers in the absence or presence of blocking or control mAbs for 30 minutes (37°C, 5% carbon dioxide, and 90% humidity). The plates were washed gently twice to remove nonadherent cells, and remaining adherent cells were quantified by counting 16 high-power fields under light microscopy. Cell adhesion to immobilized proteins. Plates containing 96 wells were coated with human fibrinogen, vitronectin, or mouse ICAM-1-Fc (20 µg/mL each) for 2 hours at 37°C and blocked with 1% (wt/vol) bovine serum albumin for 30 minutes at 25°C. Pretreated leukocytes (70 000 cells/well) or BAF3 cells were seeded in the absence or presence of blocking or control mAbs for 30 minutes. After removal of nonadherent cells by 2 washing steps, adhesion was quantified by a peroxidase reaction using p-nitrophenol as a substrate in an enzyme-linked immunosorbent assay (ELISA) reader (BioRad). Flow cytometry Blood samples were handled as described previously.20 Briefly, 1.5 mL blood was collected into a polypropylene syringe containing 0.5 mL sodium citrate, phosphate buffer, dextrose, and adenine (Greiner, Nürtingen, Germany). Immediately after blood sampling, staining with the primary mouse antihuman mAb was performed, followed by lysis of red blood cells, leukocyte fixation (lysing solution and fixing reagent from Coulter Electronics, Germany), and staining with the secondary phycoerythrin-conjugated antimouse mAb. Cells were washed twice, fixed with paraformaldehyde (1%), and analyzed on a FACScalibur flow cytometer (Becton Dickinson, Mountain View, CA). Monocytes were identified by forward- compared with side-scatter analysis. BAF3 cells were washed twice with HEPES-buffered saline before mAb staining and fixation with paraformaldehyde (1%). Nonspecific fluorescence was determined by using isotype-matched mouse IgG as the control antibody.Reverse transcriptase-polymerase chain reaction (RT-PCR) Total RNA was extracted from cells by using an RNeasy mini-kit (Qiagen, Cologne, Germany). Contaminating DNA was digested with DNase using a Message Clean kit (Gene Hunter, Brookline, MA), and 1.5 µg total RNA was transcribed to cDNA by using Omniscript RT (Qiagen) and random hexamers (Gibco BRL Life Technologies, Karlsruhe, Germany). Primer sequences for RT-PCR were as follows: uPAR (forward), 5'-GCCCTGGGACAGGACCTCTG-3'; uPAR (reverse), 5'-CATTGATTCATGGGGCCTCGGC-3'; cyclophillin (forward), 5'-CATCTGCACTG-CCAAGACTG-3'; and cyclophillin (reverse), 5'-CTGCAATCCAGCTAGGCATG-3'. PCR was performed with HotStarTaq DNA polymerase (Qiagen). Annealing temperature for uPAR and cyclophillin (internal standard) was 63°C. Real-time PCR analysis was done with a SYBR Green PCR reagents kit and an ABI Prism 7700 sequence detection system (Applied Biosystems, Foster City, CA). Each PCR amplification sample was performed with cDNA derived from 50 ng total RNA. For amplification of uPAR cDNA, the exon-spanning oligonucleotides were 5'-GCCCAATCCTGGAGCTTG A-3' and 5'-TCCCCTTGCAGCTGTAACACT-3'. Amplification of 18S ribosomal RNA cDNA was used as the internal standard; the primers were 5'-CGGCTACCACATCCAGGAA-3' and 5'-GCTGGATTACCGCGGCT-3'. Each sample was measured in triplicate, and a blank containing no template cDNA was used as the negative control.ELISA Soluble uPAR in plasma from patients was studied by using a modified ELISA described previously.21Statistical analysis Results with normally distributed continuous variables were reported as mean ± SD and were analyzed by unpaired t test or analysis of variance followed by the Scheffe test, as appropriate. In general, P < .05 was regarded as representing significance.
Up-regulation of uPAR and
Next,
Adhesion of MNCs from patients with AMI to HUVECs was significantly
inhibited by mAbs anti-CD18 (84%), anti-CD11a (51%), and anti-CD11b
(57%), indicative of the predominant contribution of Mac-1 and LFA-1
to cell adhesion (Figure 4B). Additionally, excessive cell adhesion of
AMI-MNCs to HUVECs was inhibited by the blocking anti-uPAR mAb R3 in a
dose-dependent manner (Figure 4B and 4C) but not by the nonblocking mAb
anti-uPAR R4 (Figure 4C), indicating that the total amount of
functionally active uPAR on the cell surface may limit
Consistent with the results described above, isolated MNCs from
patients with AMI showed enhanced adhesion to the adhesive ligand of
Mac-1, fibrinogen (Figure 5B). Enhanced
cell adhesion to fibrinogen in AMI samples was abrogated by mAb
anti-CD18 but also by anti-uPAR R3. Similarly, adhesion of MNCs to
immobilized vitronectin (uPAR ligand) was enhanced in AMI samples and
blocked in the presence of anti-uPAR R3 but was not affected by mAb
anti-CD18 (Figure 5A). Notably, no significant differences in cell
adhesiveness to fibrinogen or vitronectin were found between cells from
patients with CSA and cells from healthy volunteers.
Plasma from patients with AMI induces monocytic cell adhesion by
means of  2-integrin chain CD18 or mAb anti-uPAR. Thus,
apart from inducing uPAR synthesis (Figure 1D), soluble factors in AMI plasma seem to activate monocyte adhesion by means of
2-integrin and uPAR activation.
Changes in uPAR expression regulate BAF3 cell adhesion by means
of  L-chain (CD11a) and 2-chain (CD18) was
found to be virtually identical on all BAF3 cells (data not shown).
Increasing density of uPAR expression was associated with enhanced cell
adhesion to the immobilized 2-integrin ligand ICAM-1
(Figure 7) as well as to the immobilized uPAR ligand vitronectin (data
not shown). In AMI, inflammatory mediators may be involved in integrin
activation and uPAR up-regulation. These experiments show clearly that
changes in uPAR expression alone can augment
2-integrin-mediated cell adhesion independent of an
inflammatory cellular environment.
This study demonstrated that uPAR expression is enhanced on
monocytes in AMI and affects integrin-dependent and -independent cell
adhesion. In particular, uPAR surface expression on human monocytes was
up-regulated in the peripheral blood of patients with AMI. The
relevance of these changes in uPAR expression for cell adhesion was
shown with respect to the function of uPAR as both an adhesion receptor
and a coreceptor for integrins. Enhanced uPAR expression on
monocytes from patients with AMI was associated with increased cell
adhesion to the uPAR ligand vitronectin and was related to enhanced
cell adhesion to the Mac-1 ligand fibrinogen as well as to the
endothelium. Cell adhesion to vitronectin was dependent mainly on
functionally active uPAR (Figure 5A). Cell adhesion to the endothelium
was almost completely abrogated by mAbs against the
Data from previous studies using transfected Chinese hamster ovary cells indicated that uPAR could mediate cell-to-cell adhesion not only by cis interactions with integrins on the same cell surface but also by transinteraction with integrins on apposing cells.23 In our experiments, such transinteractions between uPAR and integrins may have contributed to cell adhesion on endothelium. However, the finding of cell adhesion to fibrinogen (Figure 5) excluded possible integrin-uPAR transinteractions and clearly indicated the existence of uPAR-dependent, integrin-mediated adhesion of MNCs from patients with AMI, since Mac-1 binding activity was attenuated by blockade of uPAR. The functional relevance of changes in uPAR expression was confirmed in an isolated in vitro system lacking any additional inflammatory conditions associated with AMI. In uPAR-transfected BAF3 cells, there was a strong correlation between uPAR expression and cell adhesion to vitronectin (data not shown) or ICAM-1 (Figure 7). Notably, the changes in uPAR expression that resulted in enhanced adhesiveness of transfected BAF3 cells were comparable to the differences observed between cells from patients with AMI and cells from patients with CSA. Expression of uPAR, 2-integrins.28 Factors that limit this
receptor crosstalk may include the activation status of uPAR or
integrins, the occupancy of either partner by their various soluble
ligands (uPA, uPA PAI-1, kininogen, and vitronectin),5,6,9
or possible occupancy by various known as well as unknown coreceptors
that may compete with 2-integrins for association with
uPAR (eg, gp130, 2-macroglobulin receptor, and
1-integrins such as very late antigen 4 [VLA-4] or
VLA-5).25,28 Hence, the ratio of the absolute number of
uPAR and 2-integrins does not allow any conclusions to
be drawn about the availability of uPAR for complex formations.
However, the current study clearly shows that the quantity of
expression of uPAR on resting monocytes limits
2-integrin activation, since uPAR up-regulation in AMI samples was involved in enhanced cellular adhesiveness to the endothelium. Moreover, MNCs from patients with AMI had an enhanced adhesive response to maximum stimulation with PMA, although we did not
observe any significant changes in quantitative surface expression of
Mac-1. Thus, our data suggest that enhanced availability of uPAR in AMI
may prime monocytes for enhanced adhesive responsiveness to additional
inflammatory stimuli.
Apart from its role as an integrin coreceptor, uPAR is the main receptor on monocytes that directly binds to the extracellular matrix protein vitronectin. As a consequence, enhanced binding of MNCs from patients with AMI to vitronectin was found. In previous in vitro studies, soluble vitronectin was shown to enhance leukocyte-endothelium interactions.29 Because vitronectin is an adhesive protein present in plasma as well as a major component of the vascular extracellular matrix,15 enhanced monocyte binding capacity for vitronectin might also have substantial consequences for the entire process of cell recruitment. Limitations of the study Peripheral blood from patients with AMI was obtained on admission before revascularization therapy (stent placement). Thus, revascularization therapy did not influence our results. Nevertheless, before blood samples were obtained, patients with AMI had received standard antithrombotic agents (500 mg aspirin and 5000 IU heparin) given intravenously by the referring physician or in our emergency room. In 5 patients who received prehospitalization treatment with aspirin and heparin and were subsequently found not to have an AMI, uPAR expression did not differ from that in the 2 control groups (data not shown). The use of standard therapy ( blockers, statins,
and low-dose aspirin) in patients with AMI and those with CSA was not
significantly different. Thus, different patient management measures
and prehospitalization treatment in the 2 patient groups does not
appear to have accounted for the observed differences in uPAR expression.
Pathophysiologic considerations In AMI, the adhesive phenotype of monocytes appears to be the result of a complex activation process. Soluble factors (probably inflammatory cytokines) in plasma from patients with AMI can directly activate2-integrin-mediated and uPAR-mediated
adhesion. Induced adhesion to the uPAR ligand vitronectin, the
2-integrin ligand fibrinogen, and the endothelium
depends on uPAR. Expression of uPAR on circulating monocytes is
elevated in AMI and is increased on monocytic cells on incubation with
AMI plasma ex vivo (Figure 1). The up-regulation of uPAR may result
from AMI-related processes such as hypoxia or release of inflammatory
cytokines, both of which have been shown to up-regulate uPAR in
vitro.12,30 Enhanced availability of uPAR can augment cell
adhesion by means of 2-integrins (Figure 7). The
existence of such a relation is supported by the fact that maximal
2-integrin stimulation with PMA led to enhanced integrin-mediated adhesion of AMI cells, which expressed more uPAR than
cells from patients with CSA but comparable total amounts of Mac-1
(Figure 4A).
Leukocyte recruitment is fundamental for the development of
atherosclerosis, restenosis after percutaneous coronary intervention, and myocardial damage after ischemia and reperfusion.31,32 The current study shows for the first time that uPAR has a central role
in AMI as a regulator of monocyte adhesiveness. It extends the concept
that uPAR plays a key role in
We thank M. Hölderle and T. Schmidt-Wöll for excellent technical assistance.
Submitted March 13, 2002; accepted July 2, 2002.
Prepublished online as Blood First Edition Paper, July 12, 2002; DOI 10.1182/blood-2002-03-0778.
Supported in part by grants from the Deutsche Forschungs-gemeinschaft (F.-J.N.), Wilhelm Sander-Stiftung (A.E.M.), and Novartis Foundation (K.T.P. and T.C.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Andreas E. May, 1. Medizinische Klinik und Deutsches Herzzentrum München, Technische Universität München, Lazarettstr 36, 80636 Munich, Germany; e-mail: may{at}dhm.mhn.de.
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© 2002 by The American Society of Hematology.
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  K. Viswanathan, J. Richardson, B. Togonu-Bickersteth, E. Dai, L. Liu, P. Vatsya, Y.-m. Sun, J. Yu, G. Munuswamy-Ramanujam, H. Baker, et al. Myxoma viral serpin, Serp-1, inhibits human monocyte adhesion through regulation of actin-binding protein filamin B J. Leukoc. Biol., March 1, 2009; 85(3): 418 - 426. [Abstract] [Full Text] [PDF]
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Y. Orr, J. M. Taylor, S. Cartland, P. G. Bannon, C. Geczy, and L. Kritharides Conformational activation of CD11b without shedding of L-selectin on circulating human neutrophils J. Leukoc. Biol., November 1, 2007; 82(5): 1115 - 1125. [Abstract] [Full Text] [PDF]
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S. Herold, W. von Wulffen, M. Steinmueller, S. Pleschka, W. A. Kuziel, M. Mack, M. Srivastava, W. Seeger, U. A. Maus, and J. Lohmeyer Alveolar Epithelial Cells Direct Monocyte Transepithelial Migration upon Influenza Virus Infection: Impact of Chemokines and Adhesion Molecules J. Immunol., August 1, 2006; 177(3): 1817 - 1824. [Abstract] [Full Text] [PDF]
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S. M. Kanse, R. L. Matz, K. T. Preissner, and K. Peter Promotion of Leukocyte Adhesion by a Novel Interaction Between Vitronectin and the {beta}2 Integrin Mac-1 ({alpha}M{beta}2, CD11b/CD18) Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2251 - 2256. [Abstract] [Full Text] [PDF]
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A. E. May, V. Redecke, S. Gruner, R. Schmidt, S. Massberg, T. Miethke, B. Ryba, C. Prazeres da Costa, A. Schomig, and F.-J. Neumann Recruitment of Chlamydia pneumoniae-Infected Macrophages to the Carotid Artery Wall in Noninfected, Nonatherosclerotic Mice Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 789 - 794. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
